The present invention relates generally to the field of medicine, particularly to the treatment of cancer, and more particularly, to new and useful methods for treating certain types of cancer sensitive to particular glycoside compounds.
Although molecular biology has provided new possibilities for selectively targeting and killing tumor cells without harming normal cells, current clinical chemotherapy still relies primarily on agents that kill rapidly-dividing cells regardless of whether those cells are normal or malignant.
Rapidly-dividing normal cells include cells of the bone marrow and intestine. As these are among the most rapidly-dividing normal tissues, the acute dose-limiting toxicities of most anti-cancer agents often involve bone marrow depression and gastro-intestinal side effects. Fortunately, most normal organs and tissues in humans are comprised of cells that are either slow-growing or non-proliferating, which accounts for their relative resistance to chemotherapy. Thus, the window of selectivity of the standard anti-cancer agents used today is not between normal and tumor but between rapid vs slow replicating cells. Viewing the window of selectivity in this manner highlights that the slow-growing tumor cell population found in most if not all solid tumors presents one of the most difficult obstacles to overcome in the successful treatment of the majority of human cancers with chemotherapy or radiation.
The use of glycolytic inhibitors as new chemotherapeutics to overcome this obstacle is disclosed in U.S. Pat. No. 6,670,330, issued Dec. 30, 2003, entitled “Cancer chemotherapy with 2-deoxy-D-glucose” and incorporated herein by reference. This patent discloses that the hypoxic micro-environment of the slow-growing tumor cell population within solid tumors distinguishes these cells metabolically from the majority of the normal cells in the body that are also slow-growing but under normal oxygen tension. Consequently, because hypoxia forces cells to rely primarily or exclusively on the anaerobic metabolism of glucose for survival, hypoxic tumor cells can be selectively targeted with inhibitors of glycolysis, such as 2-deoxy-D-glucose (2-DG). This patent also discloses that glycolytic inhibitors such as 2-DG can be used in combination with standard chemotherapeutic agents that target rapidly-dividing cells so that all cells in a tumor can be killed during cancer treatment. U.S. Pat. No. 6,979,675, issued 27 Dec. 2005 and incorporated herein by reference, also focuses on the use of 2-DG in the treatment of cancer and describes various combination therapies for that purpose. Clinical trials evaluating the efficacy of 2-DG in combination with docetaxel in the treatment of patients suffering a variety of solid tumors are ongoing.
Cancer therapies employing the glycolytic inhibitor 2-DG benefit from two windows of selectivity that result when a cell switches from aerobic to anaerobic metabolism, as occurs in cancer cells that become, due to tumor growth, removed from the blood (and hence oxygen) supply.
The first is that tumor cells under hypoxia up-regulate expression of both glucose transporters and glycolytic enzymes, which favors increased uptake of the glucose analog 2-DG in these cells as compared to normal cells in an aerobic environment. The second is that blocking glycolysis in normal cells in an aerobic environment does not kill those cells, because they can survive by using oxygen to burn fat and protein in their mitochondria to produce energy (via energy-storing molecules such as ATP). In contrast, when glycolysis is blocked in tumor (or normal) cells in a hypoxic environment, those cells will die, because without oxygen, those cells are unable to produce energy via mitochondrial oxidation of fat and protein.
These two windows of selectivity provide the rationale upon which better use of glycolytic inhibitors in raising the efficacy of current chemotherapy can be developed, by targeting the slow-growing hypoxic cell population found in most, if not all, solid tumors.
2-DG is known to compete with glucose for transport into the cell as well as for the binding site on hexokinase, where glucose is phosphorylated at carbon 6 in the first step of glycolysis. For 2-DG, however, the product of this step is 2-DG-6P, which accumulates intracellularly and competitively inhibits the next step in the glycolytic pathway, catalyzed by phosphoglucose isomerase, which normally converts glucose-6-phosphate to fructose-6-phosphate. Inhibition of this second step of glycolysis can prevent the cell from creating energy by anaerobic glycolysis.
Therefore, the greater the amount of 2-DG-6P produced by the hexokinase reaction, the greater the effect on glycolysis. Because 2-DG is orally available and relatively non-toxic, it is an ideal glycolytic inhibitor. However, molecular modeling of human hexokinase I interactions and experimental testing with a series of 2-halogen-substituted D-glucose derivatives has revealed that certain 2-halogen substituted glucose analogs may be as, if not more, effective than 2-DG in inhibiting glycolysis in cancer cells. These observations are consistent with the use of 2-FG (2-deoxy-2-fluoro-D-glucose) as a highly effective agent for visualizing tumors by PET scan.
While the promise of glycolytic inhibitors in the treatment of cancer is great, not all cancer cells exist in a hypoxic environment, and combination therapies are typically more difficult for both the patient and physician than therapies requiring only a single agent. There remains a need for cancer therapies that require the administration of only a single agent, particularly agents that can be orally administered in high doses, such as 2-DG and its 2-halo analogs.
Current cancer therapies are focused on the patient's illness rather than targeted to individual patients. However, interindividual differences in drug disposition or pharmokinetics have led to heterogeneity in patient responses to traditional cancer chemotherapy. There remains a need for cancer therapies that are more accurate, efficacious, and safe for individual patients. The invention meets this and other important needs.